Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia.

Abstract

CONTEXT:

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production.

OBJECTIVE:

This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD.

METHODS:

This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.

RESULTS:

Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios.

CONCLUSION:

Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

• Authors: Richard J Auchus, Kyriakie Sarafoglou, Patricia Y Fechner, Maria G Vogiatzi, Erik A Imel, Shanlee M Davis, Nagdeep Giri, Julia Sturgeon, Eiry Roberts, Jean L Chan, Robert H Farber
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 107 Issue 3 Pg. 801-812 (02 17 2022) ISSN: 1945-7197 [Electronic] United States
• PMID: 34653252 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Chemical References

• 17-alpha-Hydroxyprogesterone
• Adrenocorticotropic Hormone
• Androstenedione
• Azabicyclo Compounds
• Biomarkers
• CRF receptor type 1
• NBI 77860
• Oxadiazoles
• Receptors, Corticotropin-Releasing Hormone
• Testosterone
• crinecerfont

Topics

• Adolescent
• Adult
• Female
• Humans
• Male
• Middle Aged
• Young Adult
• 17-alpha-Hydroxyprogesterone (blood)
• Administration, Oral
• Adrenal Hyperplasia, Congenital (blood, diagnosis, drug therapy)
• Adrenocorticotropic Hormone (blood)
• Androstenedione (blood)
• Azabicyclo Compounds (administration & dosage)
• Biomarkers (blood)
• Dose-Response Relationship, Drug
• Oxadiazoles (administration & dosage)
• Receptors, Corticotropin-Releasing Hormone (antagonists & inhibitors)
• Testosterone (blood)
• Treatment Outcome